General methods for preparing microspheres normally include the steps of dissolving a biodegradable polymer carrier in a solvent, dissolving a water-soluble drug in the aqueous phase to form a first emulsion, and injecting the first emulsion into a second solution of poly(vinyl alcohol) (PVA) to form microspheres. This method is typically termed a discontinuous process. This discontinuous process is a method for preparing microspheres by injecting a first emulsion into one reactor that includes a second solution, and most commercialized processes fall under this type of discontinuous process.
Since Takeda Chemical Industries, Ltd. was granted the first patent (U.S. Pat. No. 4,652,441) relating to a discontinuous double emulsification method that led to mass production and commercialization, many related patent applications have been filed. However, such a discontinuous process produces microspheres having a very wide particle size distribution of approximately 1 to 400 μm, and has a high probability of the occurrence of microsphere aggregations or non-globular microspheres, and has difficulties in that the process parameters need to be controlled whenever increase of production scale is required for commercialization.
Poly(lactic-co-glycolic acid) (PLGA) or poly(lactic acid) (PLA), which is one of the most typical biodegradable polymer carriers, is water-insoluble and is very quickly precipitated when injected to an aqueous solution after being dissolved in an organic solvent. Using the above properties provides an advantage in that when a water-soluble drug and a polymer carrier are emulsified and then injected to a second solution, the polymer carrier can be quickly cured to form particles in which the drug can be encapsulated. However, there is a disadvantage in that the shape or the size of the particles is difficult to control since the particles are quickly cured. Particularly, when production scale and volume increase, the fast curing of particles is more difficult to control.
Generally, in order to control the fast curing of particles, a method of instantaneously applying high energy to a second emulsion by using means such as high-speed circulation of the second emulsion, homogenization, and ultrasonication, may be used. However, there are difficulties in increasing the energy to a sufficient amount in order to obtain uniform particles when the volume of the second emulsion increases proportionally with the increase of production scale.
In addition, when a second emulsion is prepared by injecting a first emulsion to one reactor to form particles, many parameters such as the injection time of the first emulsion, the temperature, the volume ratio of the first emulsion and a second aqueous solution, the concentration of a polymer carrier, the location to which the first emulsion is injected, whether the second emulsion is circulated or not, and the evaporation time of a solvent play important roles.
Therefore, increasing from a laboratory scale to a pilot or production scale is very difficult and is very often the biggest cause for failure. In addition, particles prepared by a discontinuous process have a large particle size distribution, and the size distribution also varies depending on the scale, therefore, the output of a specific preparation is not reproducible.
In view of the above, the inventors have completed the present invention by verifying that microspheres with a desired size such as a nano size can be reproducibly prepared by carrying out continuously the steps of injecting a first emulsion and a second emulsion simultaneously to form microspheres instantaneously, and applying high pressure to the above.